PROJECT SUMMARY Youth-onset type 2 diabetes (T2D) leads to early dependence on exogenous insulin and progression of T2D co-morbidities, including dyslipidemia, hypertension, non-alcoholic fatty liver disease and diabetic kidney dis- ease. The pathophysiology of T2D in youth differs considerably from adults and current treatment approaches are inadequate for youth. Thus, exploration of innovative approaches to reduce co-morbidities is critical. Meta- bolic bariatric surgery (MBS) significantly improves multiple outcomes in adults with T2D. Initial small, uncon- trolled studies of Roux-en-Y gastric bypass also suggest beneficial effects in youth with T2D, but definitive studies and understanding of mechanisms in youth-onset T2D are lacking, especially with the now more com- mon form of MBS, vertical sleeve gastrectomy (VSG). Our long-term goal is to improve the treatment of youth- onset T2D to reduce morbidity and mortality. Our central hypothesis is that VSG will be more effective in reduc- ing glycemia and comorbidities than the best currently available medical treatment: advanced medical therapy (AMT), via pancreatic, enterohepatic and/or metabolic changes. To test this hypothesis, we will enroll 90 ado- lescents with T2D across two sites and compare the effects of VSG vs. AMT on glycemic control and T2D-as- sociated comorbidities, as well as underlying mechanisms. Our sites have collaborative pediatric medical and surgical expertise, including use of non-invasive metabolic measures in MBS and T2D and collectively have a large, diverse adolescent T2D cohort, making us uniquely positioned to accomplish these aims. Our rationale is that 1) there is a critical need to determine the impact of VSG over AMT in youth-onset T2D, and 2) im- proved knowledge of the mechanisms underlying the impact of MBS will direct future non-surgical approaches to mimic MBS less invasively. Aim 1 will evaluate the effects of VSG vs. AMT on glycemic control and T2D- associated co-morbidities. We hypothesize that a higher proportion of youth with T2D receiving VSG vs. AMT will achieve the primary endpoint of HbA1c <6% with higher rates of remission (lower incidence) of comorbidi- ties at 1 and 2 years. We will also explore the impact of T2D duration, BMI, sex and initial HbA1c on the pri- mary outcome. Aim 2 will elucidate mechanisms by which VSG & AMT influence pancreatic islet cell function, enterohepatic metabolism and tissue-specific insulin sensitivity, and their contributions to glycemic control in youth with T2D. We hypothesize that the primary outcome of ?-cell function will improve in T2D youth undergo- ing VSG vs. AMT at 1 and 2 years. Secondary endpoints include whole-body IR, tissue-specific IR, incretin re- sponse and ?-cell function to understand mechanisms underlying improvements. These results will determine whether MBS is more effective than AMT in promoting glycemic control and reducing co-morbidities in youth- onset T2D, an outcome that would dramatically improve the lives of youth who currently have a dismal progno- sis. Further, this proposal will help understand the mechanisms underlying MBS in youth, to guide the develop- ment of future treatments that could target these same pathways without the need for surgery.